The present invention relates to compositions comprising biodegradable polyester oligomers, and particularly PLA/PLGA oligomers, and water soluble, low molecular weight, biodegradable block copolymers and their use for solubilizing a drug in a hydrophilic environment. Particularly, this invention relates to the use of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers to enhance the solubilizing performance of biodegradable triblock and diblock copolymers that are based on biodegradable polyester and polyethylene glycol (PEG) blocks, which are used as solubilizing agents at physiologically relevant temperatures (temperatures  less than 45xc2x0 C.).
Many important drugs have limited solubility in water, especially hydrophobic drugs. In order to attain the full expected therapeutic effect of such drugs, it is usually required that a solubilized form of the drug be administered to a patient. Recently, many peptide/protein drugs, effective for a variety of therapeutic applications, have become commercially available through advances in recombinant DNA and other technologies. Many peptide drugs are of limited solubility and/or stability in conventional liquid carriers and are therefore difficult to formulate and administer.
A number of methods for solubilizing drugs have been developed that are based on the use of solvents or cosolvents, surfactants, complexation agents (e.g., cyclodextrins, or nicotinamides), or complex drug carriers (e.g., liposomes). Each of the above methods has one or more drawbacks. Conventional surfactants and complexing agents have drawbacks of toxicity, and rapid precipitation of the solubilized drugs once administered to the patient or when otherwise diluted in an aqueous environment. Solvents and cosolvents can be toxic and irritating when injected into humans, such that the use of this solubilization approach is largely restricted to therapies for acute, life threatening diseases where medical experts are constantly in attendance to administer palliative treatments to counteract the adverse effects of the solvents/cosolvents. Water miscible solvents/cosolvents also possess the undesirable feature of allowing the drug to rapidly precipitate when an aqueous environment is contacted. Complex drug carriers, such as liposomes have limited utility due to the unstable nature of the carrier particles and the preferential uptake and localization of liposomal drugs to the reticuloendothelial system, namely, the liver and spleen.
Amphiphilic block copolymers are effective drug carriers that solubilize drugs and particularly hydrophobic drugs into an aqueous environment. For example, there are reports of amphiphilic block copolymers exhibiting self-association properties. EP No. 0 397 307 A2 (See also EP No. 0 583 955 A2 and EP No. 0 552 802 A2.) discloses polymeric micelles of an AB-type amphiphilic diblock copolymer which contains poly(ethylene oxide) as the hydrophilic B-block and poly(amino acids) as the hydrophobic A-block, wherein therapeutically active agents are covalently bonded to the A-block. Although this polymeric micelle is provided as a means of administering a hydrophobic drug, it is highly disadvantageous because it requires the introduction of functional groups into the block copolymer, and the covalent coupling of the drug to the polymeric carrier which creates new chemical entities that are impossible to fully characterize and reproducibly manufacture.
U.S. Pat. No. 4,745,160 discloses water insoluble, amphiphilic, non-crosslinked linear, branched or graft block copolymers having polyethylene glycol as the hydrophilic component and poly(D-, L-, or D, L-lactic acids) as the hydrophobic components. Although the block copolymer is described as an effective dispersing agent or suspending agent for a hydrophobic drug, the block copolymer is insoluble in water and has a molecular weight of 5,000 daltons or more. Furthermore, the hydrophilic component is at least 50% by weight based on the weight of the block copolymer and the molecular weight of the hydrophobic component is 5,000 or less. In the preparation process, a water-miscible and lyophilizable organic solvent is used. When a mixture of the polymer, the drug and an organic solvent are combined with water, precipitates are formed and then the mixture is directly lyophilized to form particles. Therefore, when this particle is dispersed in water, it forms a suspension of macroscopically visible particles.
U.S. Pat. No. 5,543,158 discloses nanoparticles or microparticles formed from a water-insoluble block copolymer consisting essentially of poly(alkylene glycol) and poly(lactic acid). The molecular weight of the block copolymer is high and the copolymer is insoluble in water. In the nanoparticle or microparticle, the biodegradable moieties of the copolymer are in the core of the nanoparticle or microparticle and the poly(alkylene glycol) moieties are on the surface of the nanoparticle or microparticle in an amount effective enough to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system. Nanoparticles are prepared by dissolving the block copolymer and drug in an organic solvent, forming an o/w emulsion by sonication or stirring, and collecting the nanoparticles containing the drug following precipitation. It does not provide for the solubilization of hydrophobic drugs. The nanoparticles are solid particles that are suspended in water.
Currently there are few synthetic or natural polymeric materials that can be used for the controlled delivery of drugs, including peptide and protein drugs, because of strict regulatory compliance requirements such as biocompatibility and low toxicity, having a clearly defined degradation pathway, and safety of the polymers and degradation products. The most widely investigated and advanced biodegradable polymers in regard to available toxicological and clinical data are the aliphatic poly(xcex1-hydroxy acids), such as poly(D-, L-, or D, L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA). These polymers are commercially available and are presently used as bioresorbable sutures. FDA-approved microsphere systems for controlled release of leuprolide acetate (Lupron Depot(trademark)) and human growth hormone (Nutropin Depot(trademark)) are also based on PLGA copolymers. Based on this history of use, PLGA copolymers have been the materials of choice in the initial design of parenteral controlled release drug delivery systems using a biodegradable carrier.
Even though there has been some limited success, PLA, PGA, and PLGA polymers present problems as drug carriers that are associated with their physicochemical properties and attendant methods of fabrication. Hydrophilic macromolecules, such as proteins may not readily diffuse through hydrophobic matrices of these polymers. Drug loading and device fabrication using PLA and PLGA often requires use of toxic organic solvents or high temperatures that denature and degrade many drugs. Also, the solid and rigid geometries of the administered solid dosage form may mechanically induce tissue irritation and damage.
There has been no previous disclosure of a composition comprising biodegradable polyester oligomers, and particularly PLA/PLGA oligomers, and low molecular weight, biodegradable triblock or diblock copolymers having a high weight percentage (at least 50 weight percent) of hydrophobic block(s) as solubilizing agents for drugs, or hydrophobic drugs in particular. Accordingly, the present invention represents improved solubilizers that minimize or are free of the problems mentioned above. It has been unexpectedly demonstrated that compositions of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers and amphiphilic, biodegradable triblock or diblock copolymers are more effective in solubilizing drugs and especially hydrophobic drugs than using the triblock or diblock copolymers alone. Biodegradable polyester oligomers, and particularly PLA/PLGA oligomers increase the solubilization capacity and stability of the drug solution thereby enhancing the efficiency and therapeutic effects of the drug. Controlling the molecular weights, compositions, and relative ratios of the hydrophilic and hydrophobic blocks of the copolymers, the composition and molecular weight of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers, and the relative amounts of copolymer and oligomer can optimize such drug solubilizing effects.
The present invention provides a biodegradable polymeric composition capable of solubilizing a drug, and particularly a hydrophobic drug, into a hydrophilic environment, and may be used in preparing a pharmaceutically effective formulation of such drugs.
The present invention also provides a method for effectively solubilizing a drug, particularly a hydrophobic drug, into a hydrophilic environment and a method for effectively administering such a drug at physiologically relevant temperatures (temperatures  less than 45xc2x0 C.) to animals by a means such as parenteral, ocular, inhalation, transdermal, vaginal, buccal, transmucosal, transurethral, rectal, nasal, oral, peroral, pulmonary, topical or aural means, although any desired route of administration may be compatible with the present invention.
The solubilizing agent of the present invention comprises biodegradable polyester oligomers, and particularly PLA/PLGA oligomers having a weight averaged molecular weight of between 400 and 10,000, and biodegradable ABA-type or BAB-type triblock copolymers, or AB-type diblock copolymers having a weight averaged molecular weight of between 2400 and 4999. The block copolymers have 50.1 to 65% by weight of the hydrophobic A polymer block(s) comprising biodegradable polyesters and 35 to 49.9% by weight of the hydrophilic B polymer block(s) consisting of polyethylene glycol (PEG). Preferably, the biodegradable polyester comprising the A-block of the copolymers, and the biodegradable polyester oligomers are synthesized from monomers selected from the group consisting of D, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, xcex5-caprolactone, xcex5-hydroxy hexanoic acid, xcex3-butyrolactone, xcex3-hydroxy butyric acid, xcex4-valerolactone, xcex4-hydroxy valeric acid, hydroxybutyric acids, malic acid, and copolymers thereof. More preferably, the biodegradable polyester is synthesized from monomers selected from the group consisting of D, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, xcex5-caprolactone, xcex5-hydroxy hexanoic acid, and copolymers thereof. Most preferably, the biodegradable polyester is synthesized from monomers selected from the group consisting of D, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, and copolymers thereof.
Polyethylene glycol (PEG) is also sometimes referred to as poly(ethylene oxide) (PEO) or poly(oxyethylene) when incorporated into a block copolymer, and the terms can be used interchangeably for the purposes of this invention.
In the case where the A-block(s) and oligomer are PLA/PLGA polyesters, the lactate content is between about 20 to 100 mole percent, preferably between about 50 to 100 mole percent. The glycolate content is between about 0 and 80 mole percent, preferably between about 0 to 50 mole percent.
The compositions of the present invention are very effective in solubilizing drugs and particularly hydrophobic drugs into water thus facilitating administration of a uniform and accurate dose at physiologically relevant temperatures (temperatures  less than 45xc2x0 C.) that may then, in many cases, enhance the therapeutic effect of the drug. For purposes of this invention, the description of the solubilized drug as a solution includes solutions of the drug in the solubilizing media at physiologically relevant temperatures (temperatures  less than 45xc2x0 C.). Solubilized drugs and drug solutions includes all free flowing forms of the compositions comprising the oligomers and copolymers of the present invention, water and drug(s) where the drug(s) is dissolved. All forms can act to facilitate administration of the drug and enhance the therapeutic effect. Such therapeutic effects may be optimized by controlling the copolymer molecular weights, compositions, and the relative ratios of the hydrophilic and hydrophobic blocks, ratios of drug to copolymer, ratios of copolymer to oligomer, and both drug and copolymer concentrations in the final administered dosage form. Additional advantages of this invention will become apparent from the following detailed description of the various embodiments.
This invention is not limited to the particular configurations, process steps, and materials disclosed herein, as such configurations, process steps, and materials may vary somewhat. It is also to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only, and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.
In this specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a composition for delivering xe2x80x9ca drugxe2x80x9d includes reference to two or more drugs. In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
xe2x80x9cEffective amountxe2x80x9d means an amount of a drug, biologically active agent or pharmacologically active agent that provides the desired local or systemic effect.
xe2x80x9cPolymer solution,xe2x80x9d xe2x80x9caqueous solutionxe2x80x9d and the like, when used in reference to a biodegradable block copolymer contained in such a solution, shall mean a water, i.e. aqueous, based composition having such block copolymer and biodegradable polyester oligomers, or particularly PLA/PLGA oligomer dissolved therein at a functional concentration. Polymer solution includes all free flowing forms of the composition comprising the oligomers and copolymers of the present invention and water. Polymer solutions act to solubilize the drug in a form that is acceptable for administration at physiologically relevant temperatures (temperatures  less than 45xc2x0 C.).
xe2x80x9cPolymeric drug delivery compositionxe2x80x9d shall mean the combination of drug, oligomer, and block copolymer.
xe2x80x9cAqueous solutionxe2x80x9d shall include water without additives or aqueous solutions containing additives or excipients such as pH buffers, components for tonicity adjustment, antioxidants, preservatives, drug stabilizers, etc., as commonly used in the preparation of pharmaceutical formulations.
xe2x80x9cDrug formulationxe2x80x9d shall include all combinations of drug with polymer, for example polymer solutions that are mixed with drug to form drug solutions, as well as mixtures of undissolved polymer with drug, i.e. polymeric drug delivery compositions, that are subsequently dissolved into an aqueous environment to form a drug solution.
xe2x80x9cDrug solutionxe2x80x9d, xe2x80x9csolubilized drugxe2x80x9d, xe2x80x9cdissolved drugxe2x80x9d, xe2x80x9csolutionxe2x80x9d and all other terms that refer to drug in a solution or dissolved state includes solutions of the drug in the solubilizing media at physiologically relevant temperatures (temperatures  less than 45xc2x0 C.). Solubilized drugs and drug solutions includes all free flowing forms of the compositions comprising the oligomers and copolymers of the present invention, water and drug(s) where the drug(s) is dissolved. All forms can act to facilitate administration of the drug and enhance the therapeutic effect.
xe2x80x9cAdministrationxe2x80x9d is the means by which drug formulations are presented to humans and animals in effective amounts, and includes all routes for dosing or administering drugs, whether self-administered or administered by medical practitioners.
xe2x80x9cParenteralxe2x80x9d shall mean administration by means other than through the digestive tract such as intramuscular, intraperitoneal, intra-abdominal, subcutaneous, intrathecal, intrapleural, intravenous and intraarterial means.
xe2x80x9cBiodegradablexe2x80x9d means that the block copolymer or oligomer can chemically break down or degrade within the body to form nontoxic components. The rate of degradation can be the same or different from the rate of drug release.
xe2x80x9cDrugxe2x80x9d shall mean any organic or inorganic compound or substance having biological or pharmacological activity and adapted or used for a therapeutic purpose.
xe2x80x9cHydrophobic drugxe2x80x9d shall mean any organic or inorganic compound or substance having biological or pharmacological activity and adapted or used for a therapeutic purpose having a water solubility less than 100 mg/mL
xe2x80x9cPeptide,xe2x80x9d xe2x80x9cpolypeptide,xe2x80x9d xe2x80x9coligopeptidexe2x80x9d and xe2x80x9cproteinxe2x80x9d shall be used interchangeably when referring to peptide or protein drugs and shall not be limited as to any particular molecular weight, peptide sequence or length, field of bioactivity or therapeutic use unless specifically stated.
xe2x80x9cPLGAxe2x80x9d shall mean a copolymer or copolymer radicals derived from the condensation copolymerization of lactic acid and glycolic acid, or, by the ring opening polymerization of lactide and glycolide. The terms lactic acid and lactate are used interchangeably; glycolic acid and glycolate are also used interchangeably.
xe2x80x9cPLAxe2x80x9d shall mean a polymer derived from the condensation of lactic acid or by the ring opening polymerization of lactide.
xe2x80x9cBiodegradable polyestersxe2x80x9d refer to any biodegradable polyesters, which are preferably synthesized from monomers selected from the group consisting of D, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, xcex5-caprolactone, xcex5-hydroxy hexanoic acid, xcex3-butyrolactone, xcex3-hydroxy butyric acid, xcex4-valerolactone, xcex4-hydroxy valeric acid, hydroxybutyric acids, malic acid, and copolymers thereof.
The present invention is based on the discovery of combining biodegradable polyester oligomers, and particularly PLA/PLGA oligomers having a weight averaged molecular weight of between 400 and 10,000, with ABA-type, BAB-type, or AB-type block copolymers, where the A-blocks are relatively hydrophobic polymer blocks comprising a biodegradable polyester, and the B-blocks are relatively hydrophilic polymer blocks comprising polyethylene glycol (PEG), having a hydrophobic content of between about 50.1 to 65% by weight and an overall block copolymer weight-averaged molecular weight of between about 2400 and 4999, and which are water soluble and capable of enhancing the solubility of drugs and hydrophobic drugs in particular, in water, to form a drug solution. It is also within the scope of the invention to include compositions where the drug is solubilized by the copolymer in an aqueous environment, yet the desired dose of the drug exceeds even this enhanced solubility state, and the final formulation of the drug has the visual appearance of a suspension or other dispersed condition, where a portion of the total drug load is dissolved and a portion of the total drug load is suspended or dispersed. With such high hydrophobic content in the block copolymers it is unexpected that such block copolymers would be water soluble. It is also an unexpected discovery that the composition of the present invention can significantly increase the water solubility and the stability of the drug solution. It is also surprising that inclusion in the present invention of an additional hydrophobic agent, i.e. biodegradable polyester oligomers, and particularly PLA/PLGA oligomers, further enhances the solubilization and the stability of drug solutions. Therefore, the composition of the present invention can be used as a solubilizing agent for the delivery of drugs and especially hydrophobic drugs, and, when administered, the hydrophobic biodegradable oligomers and polymer blocks decompose, in vivo, into non-toxic molecules. A drug may be delivered to a human or a warm blooded animal much more effectively as an aqueous solution with the biodegradable solubilizing compositions of the present invention, thus facilitating administration of a uniform and accurate dose which may in many cases enhance the therapeutic effect of the drug.
Basic to the present invention is the utilization of a block copolymer having hydrophobic A-block segments and hydrophilic B-block segments and biodegradable polyester oligomers, particularly PLA/PLGA oligomers. Generally the block copolymer will be an ABA-type or BAB-type triblock or AB-type diblock copolymer.
Both ABA-type and BAB-type triblock copolymers may be synthesized by ring opening polymerization, or condensation polymerization according to reaction schemes disclosed in U.S. Pat. Nos. 6,004,573, 6,117,949 and 6,201,072 the contents of which are fully incorporated herein by reference.
The block copolymers and biodegradable polyester oligomers, and particularly PLA/PLGA oligomers that have utility as disclosed herein meet the criteria summarized in Tables 1 and 2, respectively, namely having compositional make-up within the indicated ranges that result in block copolymers that demonstrate the desired dissolution when exposed to water. For purposes of disclosing molecular weight parameters, all reported molecular weight values are based on measurements by 1H-NMR or GPC (gel permeation chromatography) analytical techniques. The reported weight averaged molecular weights and number averaged molecular weights were determined by GPC and 1H-NMR, respectively. The reported lactide/glycolide ratios were calculated from 1H-NMR data. GPC analysis was performed on a Styragel HR-3 column, or equivalent, calibrated with PEG standards using RI detection and chloroform as the eluent, or on a combination of Phenogel, mixed bed, and 500 xc3x85 columns calibrated with PEG standards using RI detection and tetrahydrofuran as the eluent for the ABA and BAB triblock copolymers. The reported weight averaged molecular weights determined by GPC for biodegradable polyester oligomers, and particularly PLA/PLGA oligomers were conducted using an identical method with polystyrene standards. 1H-NMR spectra were taken in CDCl3 on a Bruker 200 MHz instrument.
The biodegradable polyester comprising the A-block of the copolymers, and the biodegradable polyester oligomers are synthesized from monomers selected from the group consisting of D, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, xcex5-caprolactone, xcex5-hydroxy hexanoic acid, xcex4-butyrolactone, xcex4-hydroxy butyric acid, xcex4-valerolactone, xcex4-hydroxy valeric acid, hydroxybutyric acids, malic acid, and copolymers thereof. The biodegradable polyester of the A-block of the copolymers can be the same or different from the biodegradable polyester of the oligomers. The hydrophilic B-block segment is preferably polyethylene glycol (PEG) having a weight averaged molecular weight of between about 1000 and 2000.
ABA-type and BAB-type triblock copolymers, AB-type diblock copolymers, and biodegradable polyester oligomers, and particularly PLA/PLGA oligomers may be synthesized by ring opening polymerization, or condensation polymerization. Additionally, the B-blocks may in certain instances be coupled to the A-blocks by ester or urethane links and the like. Condensation polymerization and ring opening polymerization procedures may be utilized as may the coupling of a monofunctional hydrophilic B block to either end of a difunctional hydrophobic A block in the presence of coupling agents such as isocyanates. Furthermore, coupling reactions may follow activation of functional groups with activating agents, such as carbonyl diimidazole, succinic anhydride, N-hydroxy succinimide and p-nitrophenyl chloroformate and the like.
The hydrophilic B-block is formed from PEG or derivatized PEG of an appropriate molecular weight. PEG was chosen as the hydrophilic B-block because of its unique biocompatibility, nontoxic properties, hydrophilicity, solubilization properties, and rapid clearance from a patient""s body.
The hydrophobic A-blocks and biodegradable polyester oligomers are utilized because of their biodegradable, biocompatible, and solubilization properties. The in vitro and in vivo degradation of hydrophobic, biodegradable polyester A-blocks and biodegradable polyester oligomers are well understood and the degradation products are readily metabolized and/or eliminated from the patient""s body.
Surprisingly, the total weight percentage of the hydrophobic polyester A-block, relative to that of the hydrophilic B-block, is high, e.g. between about 50.1 to 65% by weight of A-block(s), yet the resulting block copolymer retains the desirable water solubility. The total weight percentage of the biodegradable polyester oligomers, and particularly PLA/PLGA oligomers relative to the triblock or diblock copolymer is between 0.01% and 30% by weight, further increasing the hydrophobic to hydrophilic ratio of the copolymer and oligomer mixture, thus further increasing drug solubility and stability in the formulations. It is an unexpected discovery that a block copolymer with such a large proportion of hydrophobic component plus an additional hydrophobic contribution from the biodegradable polyester oligomers would be not only water soluble, but also greatly enhance the water solubility of hydrophobic drugs. It is believed that this desirable solubility characteristic is made possible by maintaining the overall weight averaged molecular weight of the entire triblock or diblock copolymer between 2400 and 4999, and the overall weight averaged molecular weight of the biodegradable polyester oligomers, and particularly PLA/PLGA oligomer between 400 and 10,000. Thus, water soluble biodegradable block copolymers capable of enhancing the water solubility of drugs and hydrophobic drugs are prepared wherein the hydrophilic B-block(s) make up about 35 to 49.9% by weight of the copolymer and the hydrophobic A-block or blocks make up about 50.1 to 65% by weight of the copolymer. The weight percentage of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers remained functional if the range was between 0.01% and 30% of the total polymer weight, where the total polymer weight is the combined weight of oligomer plus block copolymer.
The concentration in an aqueous solution at which the block copolymers are apparently soluble and capable of enhancing the water solubility of a drug may be considered as the functional concentration. Generally speaking, block copolymer concentrations of as low as 1% and up to about 50% by weight in aqueous solvents are functional. However, concentrations in the range of about 5 to 40% are preferred and concentrations in the range of about 10 to 30% by weight are most preferred. In a similar manner, the concentration of the biodegradable polyester oligomers, and particularly PLA/PLGA oligomer can be as low as 0.01% and as high as 30% of the total polymer weight and remain functional. However, concentrations of 5 to 15% of the total polymer weight are most preferred.
Drugs that may be solubilized or dispersed by the block copolymers of the present invention can be any bioactive agent, but particular advantage is achieved with bioactive agents having limited solubility or dispersibility in an aqueous or hydrophilic environment, or any bioactive agent that requires enhanced solubility or dispersibility. Without limiting the scope of the present invention, suitable drugs include those drugs presented in Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d 9th Edition or The Merck Index 12th Edition. Both volumes list drugs suitable for numerous types of therapeutic applications, including drugs in the following categories:drugs acting at synaptic and neuroeffector junctional sites, drugs acting on the central nervous system, drugs that influence inflammatory responses, drugs that affect the composition of body fluids, drugs affecting renal function and electrolyte metabolism, cardiovascular drugs, drugs affecting gastrointestinal function, drugs affecting uterine motility, chemotherapeutic agents for parasitic infections, chemotherapeutic agents for microbial diseases, antineoplastic agents, immunosuppressive agents, drugs affecting the blood and blood-forming organs, hormones and hormone antagonists, dermatological agents, heavy metal antagonists, vitamins and nutrients, vaccines, oligonucleotides and gene therapies.
Incorporating or solubilizing one or more drugs mentioned in the above categories with the mixtures of block copolymers and oligomers of the present invention to form an aqueous solution or dispersion can be achieved by simply adding the drug to an aqueous mixture of copolymer and oligomer, or by mixing the drug with the neat copolymer and oligomer and thereafter adding water to form a solution or dispersion.
The mixture of the biodegradable copolymers and oligomers with peptide/protein drugs, and/or other types of drugs, may be prepared as an aqueous drug delivery liquid that may be in the form of a solution or dispersion. This aqueous drug delivery liquid is then administered parenterally, topically, transdermally, transmucosally, inhaled, or inserted into a cavity such as by ocular, vaginal, transurethral, rectal, nasal, oral, peroral, buccal, pulmonary or aural administration to a patient. Many of the aqueously solubilized formulations prepared by implementing the present invention may be diluted in an i.v. bag or by other means, and administered to a patient, without precipitation of the drug for an extended period. The maximum concentration of the drug in solution and the period and conditions during which the drug remains in solution is often prolonged by addition of the biodegradable polyester oligomers, and particularly PLA/PLGA oligomers as compared to the ABA-, BAB-, or AB-type biodegradable block copolymers alone. This system will cause minimal toxicity and minimal mechanical irritation to the surrounding tissue due to the biocompatibility of the materials and the free flowing nature of the system at physiological temperatures ( less than 45xc2x0 C.). The A-blocks and biodegradable polyester oligomers, and particularly PLA/PLGA oligomers will be hydrolyzed or biodegraded to corresponding monomers, for example lactic acid and glycolic acid, within a specific time interval.
A distinct advantage to the compositions of this invention lies in the ability of the block copolymer to increase the solubility of many drug substances that is further enhanced by the addition of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers. The combination of the hydrophobic A-block(s) and hydrophilic B-block(s) renders the block copolymer amphiphilic in nature. This is particularly advantageous in the solubilization of hydrophobic or poorly water soluble drugs such as cyclosporin A and paclitaxel. What is surprising is the degree of solubilization into an aqueous environment of most, if not all, drugs since the block copolymer""s A-block(s) and the biodegradable polyester oligomers, and particularly PLA/PLGA oligomers are relatively hydrophobic. However, as already discussed, even though hydrophobic polymer block(s) are present in substantial amounts, the block copolymers per se are water soluble and it has been found that there is an additional increase in drug solubility with the addition of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers.
Another advantage to the composition of the invention lies in the ability of PLA/PLGA oligomers to increase the solution stability and the chemical stability of many drug substances dissolved in the solution. Various mechanisms for the degradation of drugs, that lead to a drug""s chemical instability, have been observed to be inhibited when the drug is in the presence of the composition of the present invention. For example, paclitaxel and cyclosporin A are substantially stabilized in the aqueous polymer composition of the present invention relative to certain aqueous solutions of these same drugs in the presence of organic co-solvents. This stabilization effect on paclitaxel and cyclosporin A is but illustrative of the effect that can be achieved with many other drug substances.
The biodegradable polymeric compositions of the present invention act as solubilizing agents for drugs. In one possible configuration, a dosage form comprised of a solution of the block copolymer and oligomers that contains dissolved drug is administered to the body. Before administration, the drug solution may be freeze-dried for long-term storage, and the lyophilized biodegradable polymeric drug composition may be restored to its original solution by using water or other aqueous liquid.
The only limitation as to how much drug can be dispersed in the oligomer and water soluble, biodegradable block copolymer mixtures of the present invention is one of functionality, namely, the drug:copolymer ratio may be increased until the properties of the mixture are adversely affected to an unacceptable degree, or until the properties of the system are adversely affected to such a degree as to make administration of the system unacceptably difficult. Generally speaking, it is anticipated that in most instances where dissolution is desired, the drug will make up between about 10xe2x88x926 to about 100 percent by weight of the total polymer weight (copolymer+oligomer) with ranges of between about 0.001% to 25% by weight being most common. For example, drug present at 100% by weight of the copolymer means the drug and copolymer are present in equal amounts(i.e., equal weights). Generally speaking, it is anticipated that in most instances where dispersion is desired, the upper drug copolymer ratio could substantially exceed the range noted above for dissolution. These ranges of drug loading are illustrative and will include most drugs that may be utilized in the present invention. However, such ranges are not limiting to the invention should drug loadings outside this range be functional and effective.
The present invention thus provides a biodegradable polymeric solubilizing agent for drugs and preferably hydrophobic drugs. The drug solution formed with the biodegradable polymeric solubilizing agent of the present invention has desirable physical stability, therapeutic efficacy, and toxicology.
In order to illustrate preferred embodiments of this invention, the synthesis of various low molecular weight AB-type, ABA-type or BAB-type block copolymers was accomplished and consisted of 50.1 to 65% by weight hydrophobic A-blocks (biodegradable polyesters), and 35 to 49.9% by weight hydrophilic B-block (polyethylene glycol xe2x80x9cPEGxe2x80x9d). The object was the preparation of ABA or BAB triblock or AB diblock copolymers having weight averaged molecular weights of about 2400 to 4999. The ability of PLA/PLGA oligomers to enhance the drug solubilizing functionality of the block copolymers described above was examined by preparation of PLA/PLGA oligomers with a weight averaged molecular weight between 400 and 10,000 daltons. The oligomers were mixed with copolymer to a final percentage of 0.01% to 30% of the total polymer mixture""s weight. In the case where each A-block and PLA/PLGA oligomer consist of a biodegradable polyester synthesized from monomers selected from the group consisting of D, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid, L-lactic acid, glycolide, or glycolic acid, the composition of the A-block and PLA/PLGA oligomers was about 20 to 100 mole percent lactate and 0 to 80 mole percent glycolate.
The following are examples that illustrate preferred embodiments of the invention but are intended as being representative only.